Major progress has been made over the last 10 years in understanding the immune mechanisms underlying autoimmune Type I (insulin-dependent) diabetes mellitus. It seems that immunotherapy is the best approach for preventing and/or arresting beta cell destruction. For immunotherapeutic approaches to be clinically applicable to Type I diabetes, they cannot rely on the use of non-specific immunosuppressants. Their relative ineffectiveness over the long term and the risk of recurrence, once the drug is withdrawn, requires permanent drug treatment which augments problems of infection and drug toxicity. One solution is to selectively tackle the pathogenic immune response. Operationally, this requires establishing immunological tolerance, i.e. a state of durable antigen-specific unresponsiveness in the absence of generalised immunosuppression. This review aims to present the rationale and clinical applicability of possible immunointervention strategies in Type I diabetes aimed at restoring self-tolerance to beta cells.